1. Field of the Invention
The invention generally relates to selective serotonin receptor antagonists and methods of their use as antidepressant and antianxiety agents. In particular, the invention provides spiro[9,10-dihydroanthracene]-9,3xe2x80x2-pyrrolidine (SPAN) and derivatives thereof as selective high affinity antagonists of 5-HT receptors.
2. Background of the Invention
Serotonin (5-hydroxytryptamine, or 5-HT; see Formula 1) is a product of tryptophan metabolism that mediates many diverse physiological activities. Most fundamentally, this well-characterized tryptamine derivative functions as a potent neurotransmitter by regulating G-protein coupled and ligand gated ion channel receptors at the surface of nerve and muscle cells. This activity is mediated by the binding of serotonin to several classes of cell-surface 5-HT receptors. Numerous 5-HT receptors are known and have been categorized into several families (5-HT1-5-HT7) and some are further divided into subfamilies (e.g. 5-HT2A and 5-HT2C). Many of the 5-HT receptors have been cloned and their specific functions elucidated. 
Imbalances in serotonin activity are believed to be responsible for a variety of clinically recognized disorders. For example, many brain disorders in humans are associated with fluctuations in serotonin levels and are effectively treated with drugs that interact specifically with 5-HT receptors or that block the reuptake of serotonin into the presynaptic axon terminals, suggesting that serotonin dysregulation may be involved in these disorders. For example, serotonin receptor ligands are clinically approved as drugs for the treatment of depression, psychosis, anxiety, and certain sexual aberrations, as well as for other conditions such as migraine headaches, chemotherapy-induced nausea, high blood pressure, certain abnormal cardiovascular activities and abnormal thermoregulation.
However, most of these existing agents are relatively nonselective in that they exhibit affinities for several 5-HT receptor classes, as well as for central dopaminergic, noradrenergic, histaminergic, and/or cholinergic receptors, as well as blocking serotonin and dopamine reuptake into the nerve terminus. As a consequence of activity at nonserotonergic sites, the use of these agents may result in undesirable side effects such as tardive dyskinesia, tardive dystonia, excessive weight gain, etc. These side effects can be debilitating and may require clinical treatment in and of themselves. The possibility of the occurrence of side effects is a cause of distress to patients, and is a likely contributor to patient non-compliance with suggested drug therapy regimens.
Ligands which bind with varying degrees or selectivity to some families of 5-HT receptors are known. For example, U.S. Pat. Nos. 5,496,957 and 5,504,101 to Glennon (Mar. 5, 1996 and Apr. 2, 1996, respectively, the complete contents of which are hereby incorporated by reference) describe agents which bind to the 5-HT1Dxcex2 receptor. And U.S. Pat. No. 5,942,536 to Fritz et al. (Aug. 24, 1999, the complete contents of which is hereby incorporated by reference) describes agents which bind to the 5-HT1f receptor. Roth et al. (1994) describe the binding affinities of 36 typical and atypical antipsychotic agents to 5-HT6 and 5-HT7 receptors, and Glennon et al. (1989) describe classes of agents which bind to 5-HT1A receptors. Finally, Glennon et al. (1994) describe the effect of different amine substitutions on phenylalkylamine and indolylalkylamine derivatives which bind to 5-HT2A and 5-HT2C serotonin receptors. There is an ongoing need for the development of alternative agents that selectively bind to specific families of 5-HT receptors with high affinity.
It is an object of this invention to provide compounds having the formula 
In the compounds, R1 and R2 may be xe2x80x94H, xe2x80x94OH, xe2x80x94OCH3, halogen, aryl, alkylaryl, or substituted or unsubstituted branched or unbranched C1-C10 alkyl or alkylaryl, and may be the same or different, and X may be a) carbon with two xe2x80x94H substituents, b) carbon with one or two lower alkyl substituents, or c) a heteroatom or heteroatomic group selected from the group consisting of xe2x80x94Oxe2x80x94; xe2x80x94Sxe2x80x94; or xe2x80x94SO2xe2x80x94. In some embodiments, R1 may be xe2x80x94H, xe2x80x94CH2CH2CH2Ph, xe2x80x94OCH3, xe2x80x94CH2(CH2) 4CH3, phenyl, or xe2x80x94OH. In some embodiments, R2 may be xe2x80x94H, xe2x80x94CH3 or CH2Ph. In some embodiments, X may be xe2x80x94CH2xe2x80x94, xe2x80x94C(CH3)2xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94.
Specific embodiments include compounds with the following formulas: 
The invention further provides a pharmaceutical composition comprising, a compound of formula 
in which R1 and R2 may be xe2x80x94H, xe2x80x94OH, xe2x80x94OCH3, halogen, aryl, alkylaryl, or substituted or unsubstituted branched or unbranched C1-C10 alkyl or alkylaryl, and may be the same or different, and X may be a) carbon with two xe2x80x94H substituents, b) carbon with one or two lower alkyl substituents, or c) a heteroatom or heteroatomic group selected from the group consisting of xe2x80x94Oxe2x80x94; xe2x80x94Sxe2x80x94; or xe2x80x94SO2xe2x80x94. In some embodiments, R1 may be xe2x80x94H, xe2x80x94CH2CH2CH2Ph, xe2x80x94OCH3, xe2x80x94CH2(CH2)4CH3, phenyl, or xe2x80x94OH. In some embodiments, R2 may be xe2x80x94H, xe2x80x94CH3 or CH2Ph. In some embodiments, X may be xe2x80x94CH2xe2x80x94, xe2x80x94C(CH3)2xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, and a pharmaceutically acceptable carrier.
The present invention also provides a method of treating a condition caused by abnormal serotonin activity in a patient in need thereof. The method includes the step of administering a compound of formula 
in which R1 and R2 may be xe2x80x94H, xe2x80x94OH, xe2x80x94OCH3, halogen, aryl, alkylaryl, or substituted or unsubstituted branched or unbranched C1-C10 alkyl or alkylaryl, and may be the same or different, and X may be a) carbon with two xe2x80x94H substituents, b) carbon with one or two lower alkyl substituents, or c) a heteroatom or heteroatomic group selected from the group consisting of xe2x80x94Oxe2x80x94; xe2x80x94Sxe2x80x94; or xe2x80x94SO2xe2x80x94. In some embodiments, R1 may be xe2x80x94H, xe2x80x94CH2CH2CH2Ph, xe2x80x94OCH3, xe2x80x94CH2(CH2)4CH3, phenyl, or xe2x80x94OH. In some embodiments, R2 may be xe2x80x94H, xe2x80x94CH3 or CH2Ph. In some embodiments, X may be xe2x80x94CH2xe2x80x94, xe2x80x94C(CH3)2xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94. The compound is administered in a quantity sufficient to ameliorate symptoms of said condition in said patient. The condition may be for example, clinical depression or anxiety, schizophrenia, schizoaffective disorder, and various eating and sleeping disorders. The compound may be an antagonist of 5HT2 receptors, an antagonist of H1 receptors, or an antagonist of both 5HT2 receptors and H1 receptors.
The invention further provides a method of blocking a 5HT2 receptor in a patient in need thereof. The method includes the step of administering to the patient of a compound of formula 
in which R1 and R2 may be xe2x80x94H, xe2x80x94OH, xe2x80x94OCH3, halogen, aryl, alkylaryl, or substituted or unsubstituted branched or unbranched C1-C10 alkyl or alkylaryl, and may be the same or different, and X may be a) carbon with two xe2x80x94H substituents, b) carbon with one or two lower alkyl substituents, or c) a heteroatom or heteroatomic group selected from the group consisting of xe2x80x94Oxe2x80x94; xe2x80x94Sxe2x80x94; or xe2x80x94SO2xe2x80x94. In some embodiments, R1 may be xe2x80x94H, xe2x80x94CH2CH2CH2Ph, xe2x80x94OCH3, xe2x80x94CH2(CH2)4CH3, phenyl, or xe2x80x94OH. In some embodiments, R2 may be xe2x80x94H, xe2x80x94CH3 or CH2Ph. In some embodiments, X may be xe2x80x94CH2xe2x80x94, xe2x80x94C(CH3)2xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94. The compound is administered in a quantity sufficient to block the 5HT2 receptor.
The invention further provides a method of blocking an H1 receptor in a patient in need thereof The method includes the step of administering to the patient a compound of formula 
in which R1 and R2 may be xe2x80x94H, xe2x80x94OH, xe2x80x94OCH3, halogen, aryl, alkylaryl, or substituted or unsubstituted branched or unbranched C1-C10 alkyl or alkylaryl, and may be the same or different, and X may be a) carbon with two xe2x80x94H substituents, b) carbon with one or two lower alkyl substituents, or c) a heteroatom or heteroatomic group selected from the group consisting of xe2x80x94Oxe2x80x94; xe2x80x94Sxe2x80x94; or xe2x80x94SO2xe2x80x94. In some embodiments, R1 may be xe2x80x94H, xe2x80x94CH2CH2CH2Ph, xe2x80x94OCH3, xe2x80x94CH2(CH2)4CH3, phenyl, or xe2x80x94OH. In some embodiments, R2 may be xe2x80x94H, xe2x80x94CH3 or CH2Ph. In some embodiments, X may be xe2x80x94CH2xe2x80x94, xe2x80x94C(CH3)2xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94. The compound is administered in a quantity sufficient to block the H1 receptor.
The invention further provides a method of blocking both a 5HT2 receptor and an H1 receptor in a patient in need thereof. The method includes the step of administering to the patient a compound of formula 
in which R1 and R2 may be xe2x80x94H, xe2x80x94OH, xe2x80x94OCH3, halogen, aryl, alkylaryl, or substituted or unsubstituted branched or unbranched C1-C10 alkyl or alkylaryl, and may be the same or different, and X may be a) carbon with two xe2x80x94H substituents, b) carbon with one or two lower alkyl substituents, or c) a heteroatom or heteroatomic group selected from the group consisting of xe2x80x94Oxe2x80x94; xe2x80x94Sxe2x80x94; or xe2x80x94SO2xe2x80x94. In some embodiments, R1 may be xe2x80x94H, xe2x80x94CH2CH2CH2Ph, xe2x80x94OCH3, xe2x80x94CH2(CH2)4CH3, phenyl, or xe2x80x94OH. In some embodiments, R2 may be xe2x80x94H, xe2x80x94CH3 or CH2Ph. In some embodiments, X may be xe2x80x94CH2xe2x80x94, xe2x80x94C(CH3)2xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94. The compound is administered in a quantity sufficient to block both the 5HT2 and the H1 receptor.